Specific c-Jun target genes in malignant melanoma

Schummer, Patrick; Kuphal, Silke; Vardimon, Lily; Bosserhoff, Anja‐Katrin; Kappelmann‐Fenzl, Melanie

doi:10.1080/15384047.2016.1156264

Cited by 21 publications

(16 citation statements)

References 45 publications

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“…Our data suggested that PKM2 played a significant role in promoting migration potential and invasiveness of prostate cancer cells, in part, through ERK1/2 pathway activation becausePKM2 interacted with ERK1/2 and colocalized with ERK1/2 in prostate cancer cells. c-Jun, a substrate of EKR1/2, forms the AP-1 early response transcription factor and plays a crucial role in the development and progression of cancer (42)(43)(44)(45). Previous studies have shown that cancerrelevant genes, including COX-2, are regulated by c-Jun (46).…”

Section: Discussionmentioning

confidence: 99%

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Guo

Zhang

et al. 2020

Front. Oncol.

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Pyruvate kinase M2 (PKM2) is a key enzyme of glycolysis, which is highly expressed in many tumor cells, and has emerged as an important player in tumor progression and metastasis. However, the functional roles of PKM2 in tumor metastasis remain elusive. Here we showed that PKM2 promoted prostate cancer metastasis via extracellularregulated protein kinase (ERK)-cyclooxygenase (COX-2) signaling. Based on public databases, we found that PKM2 expression was upregulated in prostate cancer and positively associated with tumor metastasis. Further analysis showed that PKM2 promoted prostate cancer cell migration/invasion and epithelial-mesenchymal transition (EMT) through upregulation of COX-2. Mechanistically, PKM2 interacted with ERK1/2 and regulated its phosphorylation, leading to phosphorylation of transcription factor c-Jun, downstream of ERK1/2, to activate COX-2 transcription by IP and ChIP assay, while inhibition of COX-2 significantly reversed the promotion effect of PKM2 on tumor metastasis in vivo. Taken together, our results suggest that a novel of PKM2-ERK1/2c-Jun-COX-2 axis is a potential target in controlling prostate cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Guo

Zhang

et al. 2020

Front. Oncol.

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“…In previous studies, we demonstrated that the transcription factor c-Jun plays a critical role in the development and progression of malignant melanoma 3,5,9,10 . However, the detailed molecular mechanism of c-Jun ’s influence on melanoma progression and development remains elusive given that only a subset of target genes is known.…”

Section: Discussionmentioning

confidence: 96%

“…AP-1 proteins bind to the classical palindromic recognition sequence 5′-TGA(C/G)TCA-3′ and regulate target gene expression, leading to deregulation of cancer-relevant signaling pathways. Thus, AP-1 transcription factor dimers play an important role in different cancer types, including malignant melanoma 1–5 . A main characteristic of AP-1 complexes in the cell is their heterogeneity in dimer composition.…”

Section: Introductionmentioning

confidence: 99%

C-Jun drives melanoma progression in PTEN wild type melanoma cells

et al. 2019

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Due to the critical impact of active AP-1 transcription factors in melanoma, it is important to define their target genes and to identify and ultimately inhibit oncogenic signals. Here we mapped the genome-wide occupancy of the AP-1 family member c-Jun in different melanoma cells and correlated AP-1 binding with transcriptome data to detect genes in melanoma regulated by c-Jun . Our analysis shows that c-Jun supports the malignant phenotype by deregulating genes in cancer-relevant signaling pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. Moreover, we demonstrate that the importance of c-Jun depends on melanoma stage and mutation status of the tumor suppressor PTEN . Our study reveals that activation of c-Jun overrules the tumor suppressive effect of PTEN in early melanoma development. These findings help to understand the relevance of c-Jun within cancer pathways in different melanoma cell types, especially in relation to MAPK and PI3K pathways, which are commonly deregulated in melanomas. Consequently, targeting c-Jun in PTEN + melanoma cells may represent a promising therapeutic strategy to inhibit survival of melanoma cells to prevent the development of a metastatic phenotype.

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“…Thus, these observations suggest that NFATC2 may act as a transcriptional break that cells need to overcome to switch to a full-blown invasive cell state. NFATC2 is itself a JUN target 77 , and may constitute a negative feedback mechanism. A similar repressor function of NFATC2 has been previously observed in breast cancer 78 .…”

Section: Recurrent Cancer Gene Network Compete With Tumor-driven Tramentioning

confidence: 99%

SCENIC: Single-cell regulatory network inference and clustering

Aibar

González-Blas

Moerman

et al. 2017

Preprint

886

1,482

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Single-cell RNA-seq allows building cell atlases of any given tissue and infer the dynamics of cellular state transitions during developmental or disease trajectories. Both the maintenance and transitions of cell states are encoded by regulatory programs in the genome sequence. However, this regulatory code has not yet been exploited to guide the identification of cellular states from single-cell RNA-seq data. Here we describe a computational resource, called SCENIC (Single Cell rEgulatory Network Inference and Clustering), for the simultaneous reconstruction of gene regulatory networks (GRNs) and the identification of stable cell states, using single-cell RNA-seq data. SCENIC outperforms existing approaches at the level of cell clustering and transcription factor identification. Importantly, we show that cell state identification based on GRNs is robust towards batch-effects and technical-biases. We applied SCENIC to a compendium of single-cell data from the mouse and human brain and demonstrate that the proper combinations of transcription factors, target genes, enhancers, and cell types can be identified. Moreover, we used SCENIC to map the cell state landscape in melanoma and identified a gene regulatory network underlying a proliferative melanoma state driven by MITF and STAT and a contrasting network controlling an invasive state governed by NFATC2 and NFIB. We further validated these predictions by showing that two transcription factors are predominantly expressed in early metastatic sentinel lymph nodes. In summary, SCENIC is the first method to analyze scRNA-seq data using a network-centric, rather than cell-centric approach. SCENIC is generic, easy to use, and flexible, and allows for the simultaneous tracing of genomic regulatory programs and the mapping of cellular identities emerging from these programs. Availability: SCENIC is available as an R workflow based on three new R/Bioconductor packages: GENIE3, RcisTarget and AUCell. As scalable alternative to GENIE3, we also provide GRNboost, paving the way towards the network analysis across millions of single cells.

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Specific c-Jun target genes in malignant melanoma

Cited by 21 publications

References 45 publications

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

C-Jun drives melanoma progression in PTEN wild type melanoma cells

SCENIC: Single-cell regulatory network inference and clustering

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